tbuckley/cabot-search huggingface dataset:
Abstract F2-3: Immunosuppressive macrophages and PARP inhibitor resistance
Authors: Jennifer Guerriero
Journal: Cancer Research (2023)

Despite objective responses to poly(ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high-dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in breast cancer susceptibility (BRCA)-associated TNBC. Macrophages are an innate immune cell that play a critical role in host defense and maintaining tissue homeostasis, however their infiltration into tumors has been associated with disease progression and resistance to therapy. Tumor associated macrophages (TAMs) represent a significant proportion of solid tumors, including breast cancer. TAMs play a major role in tumorigenesis as they can enhance tumor cell growth, angiogenesis and metastasis. In addition, TAMs can inhibit anti-tumor responses of T cells. Our recent work has shown that removal or conversion of TAMs to an anti-tumor phenotype enhances chemo- and immuno-therapy establishing TAMs as targets for anti-cancer therapy. Through multi-omics profiling, we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming, driven by the sterol regulatory element-binding protein 1 (SREBF1, SREBP1) pathway. Combining PARP inhibitor therapy with colony-stimulating factor 1 receptor (CSF1R)-blocking antibodies significantly enhanced innate and adaptive antitumor immunity and extended survival in mice with BRCA-deficient tumors in vivo, and this was mediated by CD8+ T cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate that combined PARP inhibition and macrophage-targeting therapy induces a durable reprogramming of the tumor microenvironment (TME), thus constituting a promising therapeutic strategy for TNBC. Therefore, targeting TAMs offers great potential to enhance both chemo- and immuno-therapy. Deep analysis of TAMs in solid tumors has revealed the complexity of TAMs and revealed major gaps in our knowledge of the functional and phenotypic characterization of TAM subsets associated with cancer, before and after treatment. Here we will discuss the complexity of TAMs in solid tumors including characterizing TAM subsets, location, and crosstalk with neighboring cells, as well as novel TAM-modulating strategies and combinations that are likely to enhance current therapies and overcome chemo- and immuno-therapy resistance.Citation Format: Jennifer Guerriero. Immunosuppressive macrophages and PARP inhibitor resistance [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr F2-3.
Abstract F4-1: CDK4/6 inhibitor resistance: Biological mechanisms and novel approaches
Authors: Ariella Hanker
Journal: Cancer Research (2023)

Abstract CDK4/6 inhibitors (CDK4/6i) in combination with antiestrogens have revolutionized the treatment of ER+ metastatic breast cancer (MBC), significantly prolonging survival. However, this combination is not curative in MBC, and resistance to CDK4/6i represents a major challenge. A diverse array of mechanisms of CDK4/6i resistance have been described, including deregulation of the G1/S cell cycle checkpoint (i.e. Rb, Cyclin E/CDK2, CDK6, INK4s), activation of growth factor signaling pathways (receptor tyrosine kinases, Ras/MAPK pathway, PI3K/AKT pathway), and contributions from the tumor microenvironment. A detailed understanding of these mechanisms is critical for overcoming CDK4/6i resistance. In this presentation, I will discuss recent advances in defining novel biomarkers that are causally associated with CDK4/6i resistance, therapeutic vulnerabilities linked to distinct mechanisms of resistance, and potential strategies to improve clinical responses to CDK4/6i in ER+ MBC. Citation Format: Ariella Hanker. CDK4/6 inhibitor resistance: Biological mechanisms and novel approaches [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr F4-1.
Abstract ED3-3: Oncofertility and other quality of life issues
Authors: Matteo Lambertini
Journal: Cancer Research (2023)

Abstract The current availability of effective systemic treatment strategies has significantly improved the prognosis of patients with early breast cancer. However, this survival gain is often obtained at the cost of higher toxicity. The increase in life span among breast cancer survivors calls for the need to address both early and late potential adverse effects of anticancer therapies to maximize their quality of life. Among them, the potential gonadotoxicity of anticancer therapies and its implications on fertility and ovarian function need to be discussed with all young patients. According to available guidelines, oncofertility counseling should now be considered mandatory in the care of young women with newly diagnosed cancer. This counselling should focus on the risk of developing treatment-induced premature ovarian insufficiency and on the available techniques to preserve fertility and/or ovarian function. Oocyte/embryo cryopreservation, or ovarian tissue cryopreservation in those not eligible for gamete cryopreservation, are standard strategies to be offered to young patients interested in preserving fertility, i.e. to increase their chances of post-treatment pregnancies. Ovarian suppression with gonadotrophin-releasing hormone agonists (GnRHa) during chemotherapy can be offered to premenopausal patients interested in ovarian function preservation, i.e. to decrease their risk of developing chemotherapy-induced early menopause. Current available data confirm that pregnancy occurring following proper treatment for breast cancer and period of follow-up is safe, both in terms of long-term clinical outcomes for the patients and safety for the babies. However, there is a slightly higher incidence of obstetric and birth complications that require the need for a closer monitoring of these pregnancies. Beyond fertility and pregnancy-related issues, a long-term follow-up of young women with breast cancer by the oncofertility unit is recommended for improving the management of other additional gynecological-related issues faced by these women. Among them, contraception should be considered during active treatment and in the follow-up of women who do not wish to get pregnant. Moreover, in the current era of more complex endocrine therapy approaches with a major negative impact on the quality of life of premenopausal patients with breast cancer, it is essential to properly and proactively care about their treatment-related side effects. Among them, menopause related-symptoms and sexual dysfunction may be better managed by implementing a close collaboration between oncologists and gynecologists within the oncofertility unit. Citation Format: Matteo Lambertini. Oncofertility and other quality of life issues [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED3-3.
Abstract ED8-1: Overview of the current state of the art – what patients and oncologists need to know
Authors: Rachel Jimenez
Journal: Cancer Research (2023)

Abstract While radiation therapy plays a significant role in the treatment of breast cancer for many patients, the nuances of modern day radiation therapy are often poorly understood by both patients and referring providers. Radiation therapy techniques to reduce toxicity and improve treatment accuracy have rapidly evolved in the past decade. This session will introduce non-radiation oncologists to recent innovations that allow increased personalization of treatment based on anatomical variations. Methods to improve patient positioning will be discussed. Frequently utilized dosimetric techniques for breast radiotherapy will be described and compared, including Volumetric Modulated Arc Therapy (VMAT), Intensity Modulated Radiation Therapy (IMRT), and 3D conformal planning. New methods for patient monitoring during treatment and the purpose of respiratory gating will be reviewed. Finally, the impact of surgical therapies on radiation planning and delivery will also be examined. Attendees should leave the session having a greater understanding of the current available options for radiotherapy and rationale for the choice of treatment technique. Citation Format: Rachel Jimenez. Overview of the current state of the art – what patients and oncologists need to know [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED8-1.
Abstract P1-05-17: Radiomic models based on dynamic contrast-enhanced magnetic resonance imaging predict the immunophenotype reflecting spatial distribution of CD8+ tumor-infiltrating lymphocytes in breast cancer
Authors: Seung Hyuck Jeon, So-Woon Kim, Mirinae Seo, Yu Jin Lim
Journal: Cancer Research (2023)

Abstract Purpose: This study aimed to develop noninvasive magnetic resonance imaging (MRI)-based radiomic models to predict immunophenotypes of breast cancer. Methods: A total of 182 breast cancer patients who underwent upfront surgery were analyzed, divided into training (n = 137) and validation (n = 45) cohorts. Dynamic contrast-enhanced (DCE)-MRI was acquired, and immunophenotype was determined on the surgical tumor sections: immune-inflamed (high degree of CD8+ T cells infiltrated), -excluded (CD8+ T cells accumulated at invasive margin but not efficiently infiltrated in tumor bed), and -desert (CD8+ T cells absent within tumor and at margins). Based on 833 radiomic features extracted after manual delineation, the least absolute shrinkage and selection operator method was used to build radiomic models. Results: Our radiomic models from the whole tumor sections showed moderate performance in predicting the immune-inflamed versus non-inflamed tumors, showing the highest AUC values, of 0.659 and 0.671 for training and validation cohorts, respectively. Combining the models, much improved predictability was observed, with AUC values of 0.973 and 0.985 for training and validation cohorts, respectively. Other radiomic features from tumor periphery data discriminated immune-excluded versus immune-desert status, with AUC values of 0.993 and 0.984 for training and validation cohorts, respectively. The combined models were also applicable to predicting immunophenotype for different molecular subtypes, with AUC values ≥ 0.867. Conclusions: By integrating the immunohistochemistry profiles, we established MRI-derived radiomic models to predict the detailed immunophenotype of breast cancer. This study suggests the feasibility of noninvasive assessment of tumor immune status in real-world clinics. Citation Format: Seung Hyuck Jeon, So-Woon Kim, Mirinae Seo, Yu Jin Lim. Radiomic models based on dynamic contrast-enhanced magnetic resonance imaging predict the immunophenotype reflecting spatial distribution of CD8+ tumor-infiltrating lymphocytes in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-17.
Abstract P1-05-34: MicroRNAs as Prognostic Markers in Breast Cancer
Authors: Anh Q. Nguyen, Colin Cunningham, Samuel Okpechi, Hassan Yousefi, Shawn McKinney, Brian Boulmay, Agustin Garcia, Suresh Alahari
Journal: Cancer Research (2023)

Abstract Background: Breast cancer (BC) is the most common cancer and the second leading cause of cancer death in American women. BC disproportionally affects women of ethnic minorities, especially Black and Hispanic. While this disparity has been acknowledged and social determinations of health remains an important contributor, BC pathophysiology is yet to be elucidated in minorities. MicroRNAs (miRNA), including but not limited to let-7, 125-3p, 192-5p, 451a, play regulatory roles in cancer pathobiology and progression in many cancer types, including but not limited to BC. In our lab, in vitro and in vivo studies on mouse models demonstrated that miR-23b and miR-27b had crucial roles in cancer progression in BC via mechanisms that involves nischarin, an integrin-binding protein, and were associated with worse outcome. Moreover, miRNAs can be detected and are stable in blood samples, and thus the detection has a profound clinical impact on diagnosis. Study Design: Between April 2021 and May 2022, 30 newly diagnosed patients with BC and 30 patients without any cancer diagnosis at University Medical Center- New Orleans were enrolled on the study (IRB# 936). 86% of patients are African American or Hispanics. Plasma samples were collected before any medical intervention for BC. Plasma miRNAs were isolated and miRNA expression were performed utilizing RT-PCR. Results: Expressions of let-7 and 125a miRNAs are two times higher in plasma of patients with BC compared to patients without a diagnosis of cancer. There was no difference in miRNA expression in circulatory 23b, 27b, 192-5p, and 451a. Among breast cancer types, there are two-fold decreased expression of 192-5p and 451a in triple negative compared to hormone positive BC. Conclusion: This project will add to the body of knowledge on roles of miRNAs as prognostic markers in patients with BC, more importantly, triple negative BC, and elucidate pathophysiologic mechanism contributing to racial disparity in breast cancer treatment and recurrence. In the near future, we aim to examine effects of chemotherapy and surgery on the expression of circulatory microRNAs. Citation Format: Anh Q. Nguyen, Colin Cunningham, Samuel Okpechi, Hassan Yousefi, Shawn McKinney, Brian Boulmay, Agustin Garcia, Suresh Alahari. MicroRNAs as Prognostic Markers in Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-34.
Abstract P2-24-02: Analyzing susceptibility to macrophage-activating immunotherapy bexmarilimab in breast cancer by using patient-derived tumor explants
Authors: Jenna H. Rannikko, Reetta Virtakoivu, Akira Takeda, Pia Boström, Ilkka Koskivuo, Petri Bono, Maija Hollmén
Journal: Cancer Research (2023)

Abstract The immunosuppressive tumor microenvironment governed by tumor-associated macrophages (TAMs) remains a major obstacle to effective cancer immunotherapy. A novel humanized antibody bexmarilimab, targeting the scavenger receptor Clever-1 on TAMs, has shown clinical benefit in ~40% of patients with late-stage ER+ breast cancer (MATINS; NCT03733990). To increase response rates, a comprehensive understanding on how TAM phenotype and the tumor immune landscape affect bexmarilimab-induced immune activation is needed. Single-cell RNA sequencing analysis of breast tumor macrophages shows high phenotypic variation across pathological subtypes and Clever-1 mRNA (STAB1) expression on various immunosuppressive IL4I1+ and TREM2+ monocyte-derived TAMs. STAB1 expressing macrophages were located in both lymphocyte rich and excluded areas in the tumor stroma based on digital spatial profiling with GeoMx. Due to this diversity, we studied bexmarilimab mode-of-action in breast cancer patient-derived tumor explant cultures (PDEC) by RNA sequencing and cytokine profiling. Our results show that bexmarilimab induced TNFα and CXCL10 secretion in 30-40% of the treated explants. In depth analysis of the responsive PDECs revealed a lower baseline expression of interferon responsive genes in their tumor microenvironment. Correspondingly, in vitro assays with primary human macrophages showed that chronic IFNγ priming abolished bexmarilimab-induced immune activation, suggesting potential use of bexmarilimab in patients with immunologically cold breast tumors. Citation Format: Jenna H. Rannikko, Reetta Virtakoivu, Akira Takeda, Pia Boström, Ilkka Koskivuo, Petri Bono, Maija Hollmén. Analyzing susceptibility to macrophage-activating immunotherapy bexmarilimab in breast cancer by using patient-derived tumor explants [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-24-02.
Abstract CC1-1-2: To clip or not to clip (Part 2)
Authors: Viviana Galimberti
Journal: Cancer Research (2023)

Abstract Neoadjuvant chemotherapy (NAC) changed the breast surgery approach and increased indications in recent years. NAC allows to downstage the primary tumor and also may clear the axilla of lymph node metastases in some patients. In fact, NAC allows de-escalation of surgery: not only resulted in an increase in conservative surgery in 40%, which was the initial goal of chemotherapy, but in particular it allows for a reduction in axillary surgery. Furthermore, in relation to the molecular characteristics of the tumors we can have a pathological complete response (pCR) ranging from 20 to 80%. In node-positive patients who converted to cN0 different prospective studies ACOSOG Z1071, SENTINA, SN FNAC and GANEA 2, have demonstrated that the FNR of the SNB was high, more than the acceptable 10%. Therefore, strategies to reduce the FNR treatment in cN+ patients are being investigated: is to remove more than three negative axillary lymph nodes or marking of positive axillary nodes with a tattoo or clip, the so-called target axillary dissection (TAD), to document their removal. But all the effort to reduce the FNR rate do not have clinical prognostic significance. This has already been demonstrated in the literature in different randomized trials with long term follow up. The 10-year follow-up of our study confirmed our preliminary data that the use of standard sentinel node biopsy (SNB) without the use of clip is acceptable in cN1/2 patients who become cN0 after NAT and will not translate into a worse outcome. In fact, the axillary recurrences found were less than 2% in particular in the group that started from a positive axilla were 1.8 %, if we considered that 2 of them had a micrometastatic SN and refused the AD, but if we considered only those with a negative SN the percentage drops to 0.9% Similar positive data with different follow up were also confirmed by other studies that used SNB alone without TAD. All these studies data, with now comforting results on the follow up, confirm that SN surgery alone for selected patients who have an excellent response to NAC is not oncologically inferior to AD during a short- and long-term follow-up. Citation Format: Viviana Galimberti. To clip or not to clip (Part 2) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr CC1-1-2.
Abstract ED9-2A: Can ctDNA substitute tissue testing
Authors: Ben O’Leary
Journal: Cancer Research (2023)

Abstract Circulating tumor DNA (ctDNA) is at the forefront of liquid biopsy technology. A key advantage of ctDNA is being able to achieve genomic profiling from a blood test rather than from a more invasive tissue biopsy, reducing risk and discomfort for patients as well as costs and logistical complexity. Increasing evidence supports ctDNA as a useful clinical tool in specific indications, for example in the detection of PIK3CA mutations to identify patients suitable for alpelisib plus fulvestrant.The expectation is that indications for routine ctDNA testing will expand as more data become available and ctDNA is embedded into clinical trials and paired with novel therapies. Biological and technical factors both contribute to the feasibility of ctDNA expansion into the clinic. Representation of heterogeneity might be a key strength of ctDNA analysis over tumour biopsy analysis, as sampling the circulation compartment can in principle allow representation of a wider array of disease sites than a tumor sample acquired with a single needle. However, the factors influencing how different metastases might contribute to the circulating compartment are poorly understood, presenting a challenge to clinical interpretation. Moreover, the limit of detection of ctDNA assays, the timing of treatment and stochastic effects can contribute to uncertainty, particularly in the interpretation of negative results. Recent work analyzing tumor mutational burden using ctDNA has highlighted these challenges as applied to biomarker development. Circulating tumour DNA is likely to complement tissue biopsy in the future, and may substitute tumor biopsy in specific indications supported by the data. Ultimately, clinical utility for different ctDNA indications, as opposed to tissue biopsy, will need ongoing confirmation within clinical trials. Citation Format: Ben O’Leary. Can ctDNA substitute tissue testing [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED9-2A.
Abstract P2-23-05: Trastuzumab-Induced Tumor Microenvironment Changes in Early HER2+ Breast Cancer
Authors: Laura C. Kennedy, Rebeca Alvarez, Suzanne Dintzis, Vijayakrishna K. Gadi
Journal: Cancer Research (2023)

Abstract Background Trastuzumab (H) is a critical component of therapy (tx) for HER2+ breast cancers (BCs) and can induce anti-tumor immune responses that as part of its mechanism of action. Pre-clinical studies have suggested that antibody-dependent cell-mediated cytotoxicity (ADCC) through NK cells is a major driver of the immune response. However, there is also evidence that macrophages and dendritic cells (DCs) can play an important role in H immune response through antibody-dependent cellular phagocytosis (ADCP). Here, we present pre- and post-tx gene expression and immunohistochemistry (IHC) data to characterize the tumor microenvironment (TME) changes in response to a single dose of H in patients (pts) with early HER2+ BC. Methods Pts with Stage I-III HER2+ BC with minimum 1 cm tumors were eligible. Pts received 8 mg/kg IV H followed by tissue collection. There was a minimum of 14 days between (btw) H and post-tx tissue collection. Pre- and post-tx tissues were assessed for tumor-infiltrating lymphocytes (TILs), immune-related gene expression, and AE1/3, CD31, CD4, CD8, CD11b, CD68, and CD56 expression through IHC. Results Thirteen pts were enrolled and evaluable. 5/13 were estrogen-receptor positive (ER+). TILs were assessed independently by two pathologists and the results averaged. Tx with H resulted in an increase in TILs in the post-tx tissue (p &amp;lt; 0.01). Pre-tx TILs ranged from 2-80% (median 6%) and post-tx TILs ranged from 2-80% (median 20%). 6/13 pts had immune infiltration (Inf), defined as a TIL increase of greater than 1 decile btw pre- and post-tx samples. 2/6 pts with Inf were ER+. Pts with Inf had a significantly higher DC immune signature (ISS) compared to pts without Inf (p &amp;lt; 0.01, univariate analysis). No other ISS reached significance. 6 pts had paired pre- and post-tx samples evaluated by IHC. 4/6 pts had Inf per prior definition. Pts with Inf had an increase in CD11b+ (includes macrophages and some DCs) and CD56+ cells (includes NK cells) after H tx within the tumor compartment (p &amp;lt; 0.05). Pts with Inf had an increase in CD11b+, CD56+, and CD44+ cells in the stromal compartment (p &amp;lt; 0.05). Conclusions Innate immune cells such as macrophages and DCs are key players in H-induced immune response in the early HER2+ BC TME. This data is consistent with prior pre-clinical findings. Citation Format: Laura C. Kennedy, Rebeca Alvarez, Suzanne Dintzis, Vijayakrishna K. Gadi. Trastuzumab-Induced Tumor Microenvironment Changes in Early HER2+ Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-05.